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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No OECD guideline or GLP defined. No purity of test substance defined.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2007

Materials and methods

Objective of study:
other: absorbtion, excretion
Principles of method if other than guideline:
The toxicokinetic profiles of phthalic acid (PA), were studied in rats after orally administering doses 20, 100, or 500 mg/kg.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Phthalic acid was purchased from Sigma-Aldrich (Munich, Germany), no purity defined.
Radiolabelling:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
single administration of test substance
Doses / concentrations
Remarks:
Doses / Concentrations:
20, 100, or 500 mg/kg bw by gavage in corn oil.
No. of animals per sex per dose:
3
Control animals:
not specified

Results and discussion

Preliminary studies:
no data

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The test substance was absorbed rapidly after an oral dose of 500 mg/kg bw with peak concentration (Cmax) in blood (3.5+/- 0.33 µg/ml) at 30 min postadministration.
Details on distribution in tissues:
Apparent distribution volumes pf the test substance in the steady state (Vz/F) at 20, 100, or 500 mg/kg bw were 903.28+/- 125.28, 1419.87+/-527.53, and 5264.86+/- 993.65 ml, respectively.
Transfer into organs
Transfer type:
other: no data
Observation:
other: no data
Details on excretion:
The main route of elimination following a single p.o. dose of test substance was in urine. After administering oral doses of 20,100, or 500 mg/kg bw, the test substance was excreted in urine within 24h. A larger percentage (13-26%) of test substance was excreted in urine following a single oral administration of PA (20-500 mg/kg bw). The results show that PA plasma levels in rats declined in a biphasic fashion after oral administration. The apparent distribution volume in the steady state indicates that PA is distributed extensively into tissues. The total systemic clearance of PA was moderate and significantly less than hepatic blood flow (approximately 3.91 h/kg). PA was absorbed rapidly after oral administration, and peak plasma concentrations were attained 30 min after administration. Urine analysis after the oral administration at 500 mg/kg indicated that only about 13% of unchanged PA is excreted in urine. In conclusion, the present investigation demonstrates that PA concentrations in rat plasma declined following oral administration with a mean terminal elimination half-life of about 5-6h.
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
half-life 1st: 5-6 h [20 mg/kg]
Toxicokinetic parameters:
Tmax: 0.83 +/- 0.29 (h) [20 mg/kg]
Toxicokinetic parameters:
Cmax: 4.92 +/- 0.78 (µg/ml) [20 mg/kg]
Toxicokinetic parameters:
AUC: (µg-h/ml) 44.69 +/- 2.56 [20 mg/kg]
Toxicokinetic parameters:
half-life 1st: 5.19 +/- 3.56 (h) [100 mg/kg]
Toxicokinetic parameters:
Tmax: 1.00 +/- 0.87 (h) [100 mg/kg]
Toxicokinetic parameters:
Cmax: 15.87 +/- 1.68 (µg/ml) [100 mg/kg]
Toxicokinetic parameters:
AUC: (µg-h/ml) 107.64 +/- 31.77 [100 mg/kg]
Toxicokinetic parameters:
half-life 1st: 5.10 +/- 1.19 (h) [500 mg/kg]
Toxicokinetic parameters:
Tmax: 0.67 +/- 0.29 (h) [500 mg/kg]
Toxicokinetic parameters:
Cmax: 20.49 +/- 3.64 (µg/ml) [500 mg/kg]
Toxicokinetic parameters:
AUC: (µg-h/ml) 146.90 +/- 9.33) [500 mg/kg]

Metabolite characterisation studies

Metabolites identified:
not specified
Details on metabolites:
no data

Any other information on results incl. tables

Toxicokinetic Parameters in Plasma Determined by Noncompartmental Analysis of the Time Course of Phthalic Acid (PA) Following the Oral Administration of 20, 100, or 500 mg/kg PA as a Single Dose.

 Parameters  Mean +SD
 20mg/kg  
 Tmax (h)  0.83 +0.29
 Cmax (µg/ml) 4.92 +0.78 
 Ke (1/h)  0.11 +0.02
 t1/2 (h)  5.46 +1.13
 AUC (µg-h/ml)  44.69 +2.56
 Vz/F (ml)  903.28 +125.28
 CL/F (ml/h)  97.43 +4.20
 AUMC (µg-h²/ml)  438.92 +74.15
 MRT (h)  9.79 +1.21
 100 mg/kg  
 Tmax (h)  1.00 +0.87
 Cmax (µg/ml)  15.87 +1.68
 Ke (1/h)  0.17 +0.09
 t1/2(h)  5.19 +3.56
 AUC (µg-h/ml)  107.64 +31.77
 Vz/F (ml)  1419.87 +527.53
 CL/F (ml/h)  215.01 +55.42
 AUMC (µg-h²/ml)  1003.41 +747.31
 MRT (h)  8.58 +3.83
 500 mg/kg  
 Tmax (h)  0.67 +0.29
 Cmax (µg/ml)  20.49 +3.64
 Ke (1/h)  0.14 +0.03
 t1/2(h)  5.10 +1.19
 AUC (µg-h/ml)  146.90 +9.33
 Vz/F (ml)  5264.86 +993.65
 CL/F (ml/h)  721.07 +51.81
 AUMC (µg-h²/ml)  1344.52 +325.99
 MRT (h)  9.09 +1.63

Tmax- time to reach peak plasma concentration,

Cmax-maximum plasma concentration,

Ke- Rate constant associated with the terminal phase,

t1/2- elimination half-life in plasma,

AUC- area under the concentration-time curve,

Vz/F- apparent distribution volume,

CL/F- total body clearance,

MRT- mean residence time.

Concentration of Phthalic Acid (PA) in Urine Samples After Its Oral Administration to Male Rats:

 Time interval (h)  Conc. (µg/ml)  Urine Volume (ml)  PA #1 (total amount excreted, µg)  Conc. (µg/ml)  Urine Volume (ml) PA #2 (total amount excreted, µg) Conc.(µg/ml)  Urine Volume (ml)  PA #3 (total amount excreted, µg) 
 PA-500 mg/kg                  
 0 -4  12492.67  1.0  12492.67  5814.89  2.0  11629.77  7306.40  2.0  14612.79
 4 -8  9410 .84  2.4  22586.01  12149.83  2.0  24299.65  11642.85  1.8  20957.13
 8 -12  6386.03  2.4  15326.47  5611.77  2.5  14029.43  5648.68  1.8  10167.62
 12 -16  3713.82  1.8  6684.87  5319.60  2.0  10639.20  4379.18  1.8  7882.52
 16 -24  3311.50  2.0  6622.99  1228.05  4.0  4912.18  1047.12  4.0  4188.48
 PA-100 mg/kg                  
 0 -4  4154.18  2.0  8308.35  5629.77  1.0  5629.77  4869.44  2.0  9738.87
4 -8   6369.44  2.0  12738.87  5639.02  2.5  14097.55  5425.86  2.5  13564.64
 8 -12  1441.43  2.0  2882.86  2122.93  2.5  5307.33  1880.74  3.0  5642.21
 12 -16  549.18  3.0  1647.54  1402.85  2.0  2805.70  681.56  2.5  1703.90
 16 -24  170 .06  3.0  510.17  529.60  2.0  1059.19  248.59  4.5  1118.64
 PA-20 mg/kg                  
 0 -4  558.15  2.0  1116.3  503.30  2.0  1006.59  443.29  2.0  886.58
 4 -8  375.97  2.5  939.92  313.06  2.5  782.65  380.94  2.0  761.87
 8 -12  248.87  2.0  497.74  119.10  4.0  476.39  172.43  2.5  431.07
 12 -16  138.78  2.5  346.94  158.34  2.0  316.68  70.28  4.0  281.10
 16 -24  81.80  3.0  245.39  29.17  8.0  233.37  133.37  2.0  266.73

Applicant's summary and conclusion

Executive summary:

The toxicokinetic profiles of phthalic acid (PA), were studied in rats after orally administering doses 20, 100, or 500 mg/kg. Concentrations of PA were determined in serum or urine by high-performance liquid chromatography (HPLC). The plasma concentrations of PA showed a biexponential increase following oral administration of doses ranging from 20 to 500 mg/kg. The terminal elimination half-lives (t1/2) of PA at dosages of 20, 100, or 500 mg/kg were 6.46+ 1.13, 5.19 +3.56, and 5.10 +1.10 h respectively, total clearances (CL/F) of PA at 20, 100, or 500 mg/kg were 97.43 +4.20, 215.01 +55.42, and 721.07 +51.81 ml/h, and apparent distribution volumes of PA in the steady state (Vz/F) at 20, 100, or 500 mg/kg were 903.28 +125.28, 1419.87 +527.53, and 5264.86 +993.65 ml, respectively. PA was absorbed rapidly after an oral dose of 500 mg/kg with peak concentration (Cmax) in blood (3.5 +0.33 µg/ml) at 30 min post administration. After oral administration, the dose-normalized area under the curve (AUC) (146.90 +9.33 µg/h/ml) for 500 mg/kg was significantly greater than at 20 mg/kg ( 44.69 +2.56 µg/h/ml). Urine analysis indicated that 13 +0.45% of the administered PA dose (at 500 mg/kg, p.o.) was recovered unchanged in urine within 24 h.